Our long term objectives are to elucidate peripheral receptors that can be targeted to relieve/control pain. We are focusing on metabotropic glutamate receptors (mGluRs), Group III in particular, because they produce inhibition and long term neuronal depression in the CNS. If Group III produces the same inhibitory modulation in the periphery, selective activation of Group III mGluRs on nociceptors may provide powerful and long lasting depression of noxious input. Our central hypothesis is that Group III mGluRs are integral components of peripheral sensory integration. Specifically, we hypothesize that Group III are localized on primary sensory neurons and are co-localized with TRP receptors that participate in heat (TRPV1), mechanical (TRPV4), and cold (TRPA1) transduction (aim 1). We hypothesize that activation of Group III will reduce the heat, mechanical and cold hypersensitivity that accompanies nerve-injury induced (neuropathic) pain and inflammatory pain (aim 2). We will show that the mechanism underlying reduced TRP function is related to inhibition of the cAMP/protein kinase A (PKA) pathway, an effector pathway for Group III mGluRs, as well as TRPV1, TRPV4 and TRPA1 (aim 3). In single and double label experiments, we will co-localize Group III subtypes with TRP channels in dorsal root ganglion cells and digital nerves. Ca2+ imaging studies will demonstrate the functional interaction between the Group IIIs and TRP channels. Behavioral studies and recording studies using a skin- nerve preparation will confirm the presence of Group IIIs on nociceptors and demonstrate that their activation can reduce nociceptor activity in the nerve-injured and inflamed state. The cAMP/PKA pathway will be shown as the common intracellular pathway used by Group III to modulate TRP function. The preliminary data show that Group III mGluRs can effectively reduce behavioral and neuronal responses induced by TRP activation, and relieve neuropathic and inflammatory pain. Understanding the anatomical and functional relationship between Group III mGluRs and TRP channels is critical to identifying new, non-opioid targets/approaches to treatment of chronic pain. PUBLIC HEALTH RELEVANCE: This proposal will test the overall hypothesis that activation of peripheral Group III mGluRs is an effective treatment for nerve-injury and inflammatory pain. If our hypothesis is correct, we are defining novel peripheral targets that when activated reduce peripheral sensitization and thus have functional relevance in the control of pain of peripheral origin. This family of receptors will offer a large array of extracellular and intracellular targets that are different from those associated with Group II mGluRs, and, based on our preliminary data, will be important in the modulation of hyperalgesic states.